Biopharmaceutics and Pharmacokinetics

Pharmacokinetics
  what the body does to the drug
 physicochemical properties of drug affecting biological action

Nature of Drugs
Physical Nature : solid, liquid, gas
Drug size : 100-1000 MW (mostly)
Drug-receptor Bonds : Strong covalent, Weak electrostatic, Hydrophobic
Drug shape : Chirality

Pharmacokinetic Concepts
Permeation – drug permeates through the barriers to reach its site of action

1. Passive diffusion
– uncharged molecules
– requires concentration gradient

Fick's Law of Diffusion

Rate = (C1-C2) x Permeability coefficient x Area
Thickness

2. Special carriers
– very large, charged, insoluble molecules
a. Active transport – requires energy, selective, saturable
b. Facilitated – selective, saturable

3. Endocytosis and Exocytosis

– very large, impermeant molecules
– molecule is engulfed by the cell membrane into or outside the cell

pH, pKa, Degree of Ionization

pH and Drug Transport

–only uncharged molecules can pass through passive diffusion
–most drugs are weak acids or weak basws that dissociate into charged or uncharged

pH affects physicochemical properties, and affects drug absorption:

–solubility of the drug
–lipid/water partition coefficient
–permeability of membranes
–chemical reactivity
–degree of ionization of a molecule
Henderson-Hasselbach Equation
–measure extent of ionization depending on pH pH =

pKa + log protonated/unprotonated

Weak Acid
pH = pKa + log [A-]/[AH] protonated is neutral

Weak Base
pH = pKa + log [B]/[BH+] unprotonated is neutral
pKa
– negative log of the modified equilibrium constant (Ka) for an acid-base reaction with water as the base or
proton acceptor

LIBERATION
Release of drug from its dosage form for it to be absorbed by the body
2 prerequisites for absorption:
• must be in aqueous form – to pass thru membrane
o “dissolution” – rate limiting step in absorption (exception: true solutions)
• must be in unionized form – nonpolar, ↑ lipophilicity

Factors:
• Formulations of salts for easy absorption Phenytoin Na
• Formulation of a prodrug Inactive in their native form but active in vivo
Importance:

Enhance absorption  Enalapril Enalaprilat
Facilitate drug to reach target site  Enzymes in blood (esterases) and GIT (amylase, lipase, etc.) that
may destroy or render it inactive
To alter solubility  Chloramphenicol palmitate (-16C) – ↑lipophilicity
Facilitate formulation of dosage form  Methylprednisolone – slightly water soluble
 Methylpred acetate – water insol (oint, susp)
 Methylpred Na succinate – water soluble (IV, sol)
ABSORPTION
Drug enters systemic circulation (Exemption: IV drugs)
IV > solution > suspension > capsule > tablet

Factors:
• Chemical Structure Nonpolar will be absorbed (Aminoglycosides – polar, ↓absorption)
• Particle size ↓size = ↑absorption
• Surface Area ↑surface area = ↑absorption
Amorphous > Crystalline | Anhydrous > Hydrous
• Crystalline form
Ex. Insulin Semilente Lente Ultralente
Form 100% amorphous 70% cryst., 30% amorphous 100% crystalline
Length Short Intermediate Long
Onset 5 - 15 mins 1 - 3 hrs 4 - 6 hrs
Duration 3 - 4 hrs 16 - 24 hrs >32 hrs
Examples Lispro, Aspart, Glulisine Glargine, Detemir

• Type of Tablet Coating

• Type of Tablet Matrix
• Blood flow to the absorption site
• Contact time at the absorption surface

Bioavailability (f) : the fraction of administered drug that reaches the systemic circulation unchanged

Absorption – transfer from site of administration into the system

Factors affecting absorption:
a. Drug solubility
b. Condition at site of administration
c. Circulation at site of administration
d. Area of the absorbing surface
e. Route of administration
f. Concentration of drug

Distribution – transportation of plasma-bound drug to tissues

Follows a concentration gradient: High to Low until equal conc. on both sides of the membrane
Determinants of distribution:
a. Size of the Organ
b. Blood flow – well-perfused tissues (brain, heart, kidney)
c. Solubility
d. Binding – Warfarin: strong plasma-binding | Chloroquine: strong tissue-binding

Volume of Distribution
Vd=Amt of drug in the body /plasma drug conc

Bioavailability – fraction of the drug that reaches systemic circulation

Factors influencing bioavailability:
a. First Pass Effect
b. Solubility of the drug– lipophilic but has aqueous solubility
c. Chemical instability
d. Nature of Drug Formulation
DISTRIBUTION
  Drug reaches target site
 Drug reversibly leaves the bloodstream and enters interstitium (extracellular fluid) and cells of tissues

Factors:
• Blood Flow High: heart, lungs, liver, kidneys, brain | Low: bones, skin, fat
• Capillary Permeability Liver: high | BBB: low
• Protein Binding Reservoir, prolongs duration of action
 Albumin – major drug binding protein (acidic drugs)
ɑ-acid glycoprotein – basic drug (imipramine, propranolol, lidocaine)
Problem: Displacement
- Ex. Warfarin (95%) and Phenylbutazone (98%) → bleeding

• Drug-receptor interactions
ᴥ Affinity – ability to bind
ᴥ Intrinsic binding – exert action after binding to receptor
ᴥ Agonist – has affinity and intrinsic activity
ᴥ Antagonist – affinity only

METABOLISM
o Converts drugs into polar, water-soluble products that are readily excretable
o Detoxification processes (but metabolism is not always a detoxification process)
o Factors influencing biotransformation:
a. Genetic factors
b. Environmental – concurrent drugs
c. Physiological – pediatric or geriatric

Prodrugs – compounds that are inactive in their native form, but are easily metabolized to the active agent

Examples: Primidone Phenobarbital (DOC for febrile seizures)

Phenacetin Paracetamol

First Pass Effect

 A phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it
 reaches the systemic circulation
 Only drugs administered ORALLY and RECTALLY undergo first pass metabolism
 CYP1A2 –Acetaminophen,
Caffeine, CYP2C9

CYP2C19

Phase I – Functionalization Phase CYP2D6 – antidepressant

 introduce a polar functional group (–OH, –COOH, –SH, –NH2) into a xenobiotic molecule CYP2E1

 Enzymes: microsomal Mixed Function Oxidase Systems (MFOS) or CYP3A4 (most dominant)
monooxygenases CYP450 – most important



Oxidation  Alcohols → acids
 Olefins  epoxide
 N, O, S dealkylation  NH2, OH, SH
 Aromatic
 Aliphatic
 Deamination, desulfuration, dechlorination

Reduction • Aldehyde and Ketone (Carbonyl)  alcohol

 For carbonyl, nitro, and ex. Chloral hydrate → Trichloroethanol
azo compounds • Azo and Nitro compounds  Amine
Hydrolysis For esters (acetylsalicylic acid) and amides (lidocaine)

Drugs that cause Enzyme Inducers Enzyme Inhibitors

SLE-like (CRAP GPS) (MEDICKAV)
symptoms:
Carbamazepine Metronidazole
Procainamide Rifampicin Erythromycin
Isoniazid Alcoholism (chronic) Disulfiram
Methyldopa Phenobarbital INH
Chlorpromazine Griseofulvin Cimetidine
Hydralazine Phenytoin Ketoconazole
Smoking/St. John’s wort Acute alcoholism
Valproic acid (Depakene)
Phase II – Conjugation Phase

• attach small, polar, ionizable endogenous compound to the functional handles of Phase I water soluble
• usually but not always result to inactive compounds – ex. morphine-6-glucuronide (more potent and active)

Cosubstrate Enzyme Substrates

Glucuronidation
Most common,
Not developed in neonates
Sulfate Conjugation
Developed in neonates
Methylation
Does not lead to polar or
water-soluble metabolites
Acetylation
Does not lead to polar or
water-soluble metabolites
Function: termination
pharmacologic action
detoxification
Glycine Conjugation
Glutathione Conjugation
Tripeptide GSH:
Glycine
Cysteine
Glutamic acid
Uridine diphosphate UDP-glucuronyltransferase Paracetamol
glucuronic acid (UGT) Chloramphenicol
(UDP-glucuronic acid) Bilirubin
Steroid hormones
Thyroid hormones
3’-phosphoadenosine- Sulfotransferases Phenols
5’phosphosulfate (PAPS) Alcohol
Aromatic amines
Paracetamol
S-adenosylmethionine (SAM) Phenol-O-methyltransferase Catecholamines
(POMT)
Phenylethanolamine methyl
Catechol-O- transferase (PEMT) –
methyltransferase (COMT) converts NorEpi to Epi
Acetyl-coenzyme-A N-acetyltransferase X containing aromatic amine
NAT 1 (tissues) or hydrazine group:
NAT 2 (liver & intestine)
Hydralazine
of Isoniazid
or Procainamide
Aminoacyl-tRNA synthetases For carboxylic acids
(needs ATP) Benzoic → Hippuric acid
Glutathione-S-transferase Paracetamol toxicity because
of↓ glutathione
- limit: 4g/day
- antidote: N-
acetylcysteine (Fluimucil)
EXCRETION – final loss of drugs from the body
o The main route of excretion of a drug and its metabolites is through the kidney
Renal Excretion
1. Glomerular Filtration
2. Active Tubular Secretion
3. Passive Tubular Reabsorption

Enterohepatic Circulation (biliary recycling)

 phenomenon in which drugs emptied via bile into the small intestine can be reabsorbed in the intestinal lumen
 back into circulation
  extends duration of action and t ½
 Carbamazepine – anticonvulsant (DOC for post-herpetic neuralgia/tic douloureux/trigeminal neuralgia)

Isosterism
 describes the selection of structural components, the steric electronic, and solubility characteristics of a drug
which make it interchangeable with drugs of the same pharmacologic class

Isosteres
 compounds or group of atoms having the same number and arrangement of electrons

 group of atoms that impart similar physical and chemical properties to a molecule, because of similarities in size,
electronegativity, or stereochemistry

 compounds may be altered by isosteric replacements of atoms or groups, to develop analogues with select
 biologic effects, or to act as antagonist to normal metabolites
 Example: replacement of the hydroxyl group of folic acid by an amino group

Elimination
First-order elimination
Rate of elimination is proportionate to concentration
Concentration decreases exponentially

Zero-order elimination
Elimination is constant regardless of concentration
Concentration decreases in linear fashion
ex. Phenytoin, Aspirin
Clearance (renal, liver, systemic, other) = concentration / rate of elimination
Half-life (t ½) = (0.693 x Vd) / clearance
 Route Onset Indication Example
Topical ointment 1 hour Local on skin, eye, ear Cream
Oral 30-60 min Safe & convenient Tablet, capsule
Intradermal 30-60 min Long & continuous Contraceptive
Vaginal suppositories 15-30 min Local effect Cream, foam
Rectal 15-30 min Local effect Laxative
Sublingual Few min Rapid effects Nitroglycerin
Buccal Few min Convenient Androgens
SC Few min GI sensitive drigs Insulin, epinephrine
IM Few min GI sensitive drugs Narcotic, antibiotic
Intrathecal Few min Spinal cord effects Anesthesia
Intravenous 1 min Rapid & high absorption IV fluid, antibiotic
Intraarterial 1 min Local internal organ Cancer drugs
Inhalation 1 min Local respirator Antiasthma